Methods of preventing or treating diseases and conditions using complex carbohydrates

ABSTRACT

The invention relates to a method of preventing and treating diseases and conditions associated with allergies, autoimmunity, the adhesion cascade, the metastatic cascade or the coronary cascade comprising administering (i) at least one complex carbohydrate as the sole active ingredient, or (ii) at least one pharmaceutical composition which comprises as an active ingredient a pharmacologically effective amount of at least one low purity or cosmetic grade complex carbohydrate selected from the group consisting of oligosaccharides, sialylated oligosaccharides, polysaccharides and glycosaminoglycans, and an effective amount of at least one transdermal or transmucosal carrier in an amount effective to deliver the complex carbohydrate into the blood stream.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority under 35 U.S.C. 119 ofProvisional Application No. 60/222,046 filed Jul. 31, 2000, which isherein incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates to novel uses for a composition of mattercomprising complex carbohydrates preferably as the sole activeingredient, applied topically, orally, mucosally or parenterally toprevent or treat diseases and conditions associated with allergies orthe adhesion, metastatic or coronary cascades. Also disclosed aremethods of preventing and treating the above-mentioned diseases andconditions by administering the complex carbohydrates of the presentinvention. Additionally, this invention describes novel uses for acomposition of matter comprising at least one complex carbohydrate andat least one transdermal or transmucosal carrier useful for effectingtransdermal or transmucosal migration resulting in topical or mucosaldelivery of macromolecules, through the skin or mucous membranes ofmammals and into the bloodstream. Methods of preventing diseases andconditions of mammals associated with allergies, autoimmune mechanisms,the adhesion cascade, the metastatic cascade and the coronary cascadeare also described wherein the combination of complex carbohydrates withessential oils is applied topically, orally, mucosally or parenterallyon a repeated basis until treatment is complete.

BACKGROUND OF THE INVENTION

[0003] For purposes of this invention, complex carbohydrates are definedas any polymer comprising more than two sugar moieties and include suchclasses of compounds as polysaccharides and oligosaccharides.Polysaccharides include mucopolysaccharides and mannans whereasoligosaccharides are comprised of branched polysaccharides such assialylated sugars including milk sugars. The key milk sugars (alsocalled hexaoses) incorporated in the general class of complexcarbohydrates are difucosyllacto-N-hexaose a and b,Disialyl-monofucosyllacto-N-hexaose and monofucosyllacto-N-hexsaose I,II, and II (obtainable from Oxford Glycosystems, Inc.).

[0004] One of the most active areas of research at present is the studyof the genetics and function of mucopolysaccharides. These areglycosaminoglycans that can be obtained from numerous sources (e.g.rooster combs, trachea, umbilical cords, skin, articular fluids andcertain bacteria such as Streptococci spp). Most glycosaminoglycans(hyaluronic acid, chondroitin sulfates A, B, and C, heparin sulfate,heparin, keratan sulfate, dermatan sulfate, etc.) are composed ofrepeating sugars such as n-acetylglucosamine, glucuronic acid andn-acetyl galactosamine (these are known as non-sulfatedglycosaminoglycans). If such glycosaminoglycans contain sulfur groupsthey are known as sulfated glycosaminoglycans.

[0005] Heparin, hyaluronic acid and chondroitin sulfate are the moststudied mucopolysaccharides. Heparin has been used for a number of yearsas an anticoagulant. Hyaluronic acid has been used therapeutically sincethe 1970s as a replacement for the vitreous humor of the eye postsurgery and, more recently, as replacement for joint fluid in arthriticjoints. The mode of action for hyaluronic acid injected directly intojoints for treatment of arthritis has been proposed to be lubricationand replacement of the degraded joint fluid with highly viscoushyaluronic acid. High molecular weight (>750,000 daltons) and highviscosity have been reported to be critical for this use. (For purposesof this patent, all molecular weights are expressed as daltons. The unitdesignation will not be added hereinafter.) In the 1980s, it wasdiscovered that chondroitin sulfate, or polysulfated glycosaminoglycan(known by its commercial name as ADEQUAN®) could be injectedintramuscularly for reduction of pain and inflammation associated witharthrosis of horses. The mechanism of action of this glycosaminoglycanhas been speculated to be inhibition of certain degradative enzymespresent in the joint fluid that are up-regulated by trauma.

[0006] In the 1990s, chondroitin sulfate had developed into a popularnutritional supplement being used extensively to treat joint problems.Such treatment requires oral doses between 1000 and 3000 mg/day forhumans. Even with these high doses (>15 mg/Kg), relief from joint painoften takes 6-9 months.

[0007] In 1989, it was discovered that intravenous, intramuscular orsubcutaneous delivery of hyaluronic acid could reduce the pain ofarthritis (U.S. Pat. No. 4,808,576 by Schultz et al) when the hyaluronicacid was delivered remote to the site of the arthritis (not into thejoint). This Schultz et. al. patent specifically states that thehyaluronic acid must be of high purity (>99% pure hyaluronic acid). Nomention is made of use of other complex carbohydrates,mucopolysaccharides or glycosaminoglycans administered by any method, oruse of hyaluronate sodium orally or mucosally, use of low purityglycosaminoglycans or treatment of other diseases or conditions byparenteral administration.

[0008] The importance of high molecular weight for effectiveness ofhyaluronic acid in the treatment of arthritis is generally emphasized(see for example Balazs, U.S. Pat. No. 4,141,973 and Howard andMcIlraith, The Compendium, 15(3), March 1993) who summarize severalclinical studies conducted to determine the most efficacious molecularweight range of hyaluronic acid injected intra-articularly to treattraumatic arthritis in horses. The conclusion from these studies wasthat hyaluronic acid with a molecular weight below 1×10⁶ was not aseffective as hyaluronic acid with a molecular weight above this value.

[0009] The most recent studies on hyaluronic acid discuss treatment ofvarious types of cancer with very large doses of this macromolecule(Falk, WO 97/40841). This Falk application suggests that doses shouldexceed 750 mg per 70 Kg person, preferably, exceeding 1 g per 70 Kgperson. This dose level calculates to be approximately 10-20 mg/Kg. Suchdoses are given intermittently post diagnosis and are not suggested tobe preventative or administered in continuous low doses. Additionally,it is clear that the sodium hyaluronate of the Falk invention needs tobe pure enough for injection even though oral administration is used inaddition to intravenous injection. In all cases, patients were treatedwith hyaluronan in addition to chemotherapy. Hyaluronan was not used asthe sole active ingredient for treatment of the cancer patients by Falk.

[0010] The adhesion cascade was first described in the early 1990s. In asummary by Adams and Shaw (The Lancet, 343, Apr. 2, 1994) the adhesioncascade is supposed to describe the mechanism by which pain and swellingare produced post trauma. It is divided into four sequential steps oftethering, triggering, strong adhesion and motility. Tetheringinteractions are mediated by a family of three lectin-likecarbohydrate-binding molecules (selecting) These interactions are strongenough to cause the leukocytes to roll along the blood vessel walls tothe site of trauma instead of flowing freely through such vessels asthey would in a non-traumatized state. The triggering response isstimulated by factors such as cytokines stimulated by a traumatic eventand mediated by adhesion molecules called integrins. Integrins, bythemselves, do riot bind well to epithelium. However, when activated,integrins promote strong adhesion of the leukocyte to the epithelialsurface Leukocytes bind to the epithelial cells via their receptor sitessuch as CD44, CD31, etc. By a mechanism of attachment and detachment theleukocytes are guided to the site of trauma. At the site of trauma theadhesion to the blood vessel wall becomes stronger and the interactionof these integrins with their ligands on the surface of the leukocytesare responsible for cessation of movement and flattening of theleukocyte. Finally, a process involving VCAM-1 and LFA-1 and other suchintegrins allows leukocytes to pass between endothelial cell junctionsand into the tissue that has been traumatized. Collection of leukocytesat the site of trauma produces inflammation which is then followed bypain or other sequelae.

[0011] The metastatic cascade is very similar to the adhesion cascade.It has been proposed that tumor cells of all types contain CD44 receptorsites on their surface. These CD44 receptor sites appear to be involvedin metastasis functioning similar to the receptor sites on leukocytestethering the tumor cells to the blood vessel wall and providing themotility necessary for movement from one site to another in themammalian body. A significant portion of the literature on CD44 andtumor cells/cancer teaches that hyaluronic acid or hyaluronan actuallystimulates metastasis (Eur. J. Cancer, 1999, March; 35 (3), 473-480).

[0012] A coronary cascade has recently been described in the HarvardHealth Letter (December 1999, pg. 4-5) and SCIENCE vol:285, Jul. 23,1999, pg 595-599). This cascade describes a new mechanism to explain thedevelopment of heart disease and stroke. Rather than the traditionaltheory that plaques are formed by a collection of cholesterol alone, thenew theory is based on the premise that there are stable and unstableplaques produced on blood vessel walls. Unstable plaques are the problemplaques because they are “swarming with T cells and macrophages” thatare responding to a site of trauma and triggering the adhesion cascaderesulting in inflammation. It is the “swarming T cells and macrophages”that make these plaques unstable. The T cells are described as sendingmacrophages a signal to release a protein called tissue factor which“spills out and encounters circulating blood, attracting platelets andtriggering formation of a clot that quickly blocks up the artery”.

[0013] Accordingly, it is totally unexpected that complex carbohydratesof the present invention could be administered topically, orally,mucosally or parenterally, in low doses, to prevent and treat diseasesand conditions associated with allergies, the adhesion cascade, themetastatic cascade and the coronary cascade described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 is a graph demonstrating the effect of treating an adultsuffering with Attention Deficit Disorder with various formulations ofhyaluronic acid.

[0015]FIG. 2 is a graph demonstrating the effect of treating a 9 yearold child suffering from Attention Deficit Hyperactivity Disorder withhyaluronic acid.

SUMMARY OF THE INVENTION

[0016] The present invention relates to a method of preventing andtreating diseases and conditions associated with allergies,autoimmunity, the adhesion cascade, the metastatic cascade or thecoronary cascade comprising administering (i) at least one complexcarbohydrate as the sole active ingredient, or (ii) at least onepharmaceutical composition which comprises as an active ingredient apharmacologically effective amount of at least one low purity orcosmetic grade complex carbohydrate selected from the group consistingof oligosaccharides, sialylated oligosaccharides, polysaccharides andglycosaminoglycans, and an effective amount of at least one transdermalor transmucosal carrier (e.g. essential oil) in an amount effective todeliver the complex carbohydrate into the blood stream.

[0017] Accordingly, the present invention relates to using complexcarbohydrates, including but not limited to mucopolysaccharides andglycosaminoglycans, to bind to the receptor sites on leukocytes (e.g.CD44 and CD31) blocking their ability to tether to the blood vesselwalls, inhibiting the motility to the site of trauma thus reducing thepain, swelling and other sequelae associated therewith (interrupting theadhesion cascade). Additionally, the present invention teaches thatcomplex carbohydrate molecules, including but not limited tomucopolysaccharides and glycosaminoglycans, bind to the receptor siteson tumor cells blocking their ability to tether to the blood vesselwalls and inhibit the tumor motility which, in turn, inhibits thepotential for metastasis.

[0018] The compositions of the present invention inhibit the macrophagesfrom swarming to a site of irritation or trauma on a blood vessel wallwherein said macrophages would normally accumulate producing theunstable plaques described previously, thus preventing and treatingheart disease and stroke. Additionally, the compositions of the presentinvention inhibit the T-cell and macrophage “swarming” thus blocking therelease of the tissue factor (referred to previously) and preventingcardiac events caused by said ruptured plaques.

[0019] In another embodiment of the present invention allergies andallergy-related diseases, diseases associated with the bodies' adversereactions to stimuli such as foods, inhalants and drugs wherein saidadverse reactions include but not limited to Attention Deficit Disease,Attention Deficit Hyperactivity Disease, interstitial cystitis, autism,migraines, asthma, Turret's Syndrome, fibromyalgia, anaphylaxis,rhinitis, sinusitis and inflammation providing the environment for yeastinfections, bacterial infections or virus infections and autoimmunediseases wherein the bodies' macrophages attack its own body tissues andorgans producing diseases including but not limited to rheumatoid andosteoarthritis, Lupus Erythematosis, multiple sclerosis, polymyositis,muscular dystrophy, Diabetes, and potentially Alzheimer's Disease, areassociated by a mechanism similar to the adhesion cascade. Therefore,CD44, CD31, RHAMM and other similar receptors are involved in producingthe allergic reaction and the autoimmune response. Again, the binding ofcomplex carbohydrates to these receptor sites inhibit the reactionand/or response. Therefore, allergies, allergy-related diseases andautoimmune diseases respond to treatment by oral, mucosal, topical andparenteral administration of complex carbohydrates as described herein.

[0020] One of the most recent theories to explain the significantneurological degeneration that occurs in Alzheimer's Disease involves asubstantial inflammatory component (SCIENCE, vol: 286, Dec. 17, 1999,pgs 2352-2355) which is concluded herein to be related to the adhesioncascade. Therefore, the present inventors have found that the complexcarbohydrates of this invention can be used to prevent and/or treatAlzheimer's Disease. Another explanation for the development of dementiaand Alzheimer's Disease is that an amyloid protein is produced in thebrain resulting in the formation of amyloid plaques that lead toneuronal degeneration. The neuronal degradation is associated withdiseases related to various types of dementia including but not limitedto Alzheimer's Disease. Since it is known that CD44 is present insignificant amounts on neuronal cells in the brain, the complexcarbohydrates of the present invention bind to CD44 and/or otherreceptor sites in the brain and inhibit the formation of such amyloidplaques.

[0021] Accordingly, although not bound by any theory, the inventionrelates to a composition of matter comprising complex carbohydratespreferably as the sole active ingredient, applied topically, orally,mucosally or parenterally to prevent and treat diseases and conditionsassociated with allergies, autoimmunity, and the adhesion, metastatic orcoronary cascades. However, the compositions described in U.S. Pat. No.5,888,984 and in PCT/US00/02328 may also be utilized in the methods ofthe present invention.

[0022] Additionally, this invention describes a composition of mattercomprising at least one complex carbohydrate and at least onetransdermal or transmucosal carrier useful for effecting transdermal ortransmucosal migration of said complex carbohydrate, resulting intopical or mucosal delivery of said molecules, through the skin ormucous membranes of mammals and into the bloodstream in order to preventor treat the diseases and conditions associated with allergic reactions,the adhesion cascade the metastatic cascade or the coronary cascade.Transdermal carriers are those compounds that allow molecules, includingmacromolecules to pass through the skin and into the blood stream ofmammals. Transmucosal carriers are those compounds that allow moleculesincluding macromolecules to pass through the mucous membranes and intothe blood stream of mammals. A patch or bandage can be embedded with thecomplex carbohydrates of the present invention so as to extend deliveryof the molecules and/or provide slow release over several days. In theuse of the complex carbohydrates of the present invention in bandages,they can be used without the presence of transdermal or transmucosalcarriers with open wounds, or containing said carriers when used totreat closed wounds or reduce scarring or scar tissue.

[0023] This invention further describes a method of preventing andtreating diseases and conditions of mammals associated with allergies,autoimmunity, the adhesion cascade, the metastatic cascade or thecoronary cascade comprising administering a composition of complexcarbohydrates topically, orally, mucosally or parenterally preferably ona repeated basis (e.g. 2 times per day, preferably 4 times per day, andmost preferably 8 times per day, or simply “as needed”).

[0024] Applications of the present invention would be made on a repeatedbasis for the term of the disease or condition or as long as necessaryto prevent the diseases or condition from progressing, or to treat thediseases or conditions until they are resolved.

[0025] Finally, this invention describes a mechanism by whichinflammation, including diseases and conditions associated therewith,tumor growth, tumor metastasis, allergies and allergy-related diseases,autoimmune diseases, coronary diseases and central nervous systemdiseases can be prevented or treated by administering complexcarbohydrates topically, orally, mucosally, or parenterally.

[0026] It is understood that this invention describes the prevention andtreatment of numerous diseases and conditions including but not limitedto arthritis (osteoarthritis and rheumatoid arthritis), gastritis,stomach or intestinal ulcers, colitis, esophagitis, bronchitis, thecommon cold, rhinitis, sore throat, tonsillitis, tendonitis,fibromyalgia, chronic fatigue syndrome, interstitial cystitis,polymyositis, autism, Lupus Erythematosis, headaches includingmigraines, pancreatitis, anaphylaxis, vaginitis, hemorrhoids, sunburn,heat burns, temporomandibular joint (TMJ) condition, gingivitis, dentalcaries, dental pain, post surgical pain, menstrual pain, extremitycramps, pre and post partum pain, itching associated with allergies andhypersensitivity (e.g. poison ivy, oak and sumac and eczema), asthma,emphysema, Attention Deficit Disorder, Attention Deficit HyperactivityDisorder (ADHD), fibromyalgia, Turret's Syndrome, Multiple Sclerosis,Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease, Parkinson'sDisease, high blood pressure, heart disease, heart attack, vasculitis,stroke, increased degradation of spinal nerves post spinal cord injury,head or brain trauma post injury, adhesion formation post surgery orchemotherapy, scar formation post surgery, non-healing wounds, decubutisulcers, irritation of nerve bundles (e.g. trigger points) ganglionformation, dementia including but not limited to Alzheimer's disease,Human Immunodeficiency Virus infection (HIV), yeast infections,bacterial infections, viral infections, encephalitis, epilepsy,meningitis, peripheral neuropathy, Creuztfeldt-Jacob Disease, Bell'sPalsy, cognitive disorder, cancer, Diabetes, skin problems such as acne,lick granulomas, hot spots, psoriasis, rashes, wrinkles, and even hairloss.

[0027] Such prevention and treatment are accomplished by topically,orally, mucosally or parenterally applying complex carbohydrates of thepresent invention to mammals in an amount and number of applications soas to be effective in preventing and treating the target disease orcondition. It is understood that such prevention or treatment results inblockage of receptor sites associated with allergies, autoimmunemechanisms, the adhesion cascade, metastatic cascade, or coronarycascade.

DETAILED DESCRIPTION OF THE INVENTION

[0028] This invention describes novel uses for a composition of mattercomprising at least one complex carbohydrate that is applied topically,orally, mucosally or parenterally to prevent and/or treat diseases andconditions associated with allergies, autoimmunity, the adhesioncascade, the metastatic cascade or the coronary cascade. The inventionalso encompasses novel uses for a composition comprising at least onecomplex carbohydrate and at least one transdermal or transmucosalcarrier. The invention also preferably encompasses novel uses for acomposition of matter comprising complex carbohydrates as the soleactive ingredient. Further, the compositions disclosed in U.S. Pat. No.5,888,984 and in PCT/US00/02328 (including provisional applications60/117,988 filed Feb. 1, 1999, No. 60/127,749 filed Apr. 6, 1999, No.60/137,098 filed Jun. 2, 1999, No. 60/142,306 filed Jul. 3, 1999 and60/166,326 filed Nov. 19, 1999 on which priority is based inPCT/US00/02328) may also be utilized in the methods of the presentinvention.

[0029] More specifically, the present invention is directed to a methodof preventing and treating diseases and conditions associated withallergies, autoimmunity, the adhesion cascade, the metastatic cascadeand the coronary cascade comprising administering said complexcarbohydrates to the affected mammal topically, orally, mucosally orparenterally. A significant feature of this invention is that thecomplex carbohydrates are preferably administered in a low dose. By lowdose is meant from 0.000001 mg/kg to 150 mg/kg, preferably from 0.001mg/kg to 100 mg/kg and more preferably from 0.01 mg/kg to 20 mg/kg.

[0030] The invention also describes a method for reducing the sequelaeof trauma in irritated or inflamed tissue of mammals by the topical ormucosal application of a mixture of a transdermal or transmucosalcarrier and one or more complex carbohydrates or mixtures thereof. Thecomposition described is applied directly on or over the traumatizedsite or on a mucous membrane.

[0031] Finally, the invention describes a method for reducing thesequelae of trauma in irritated or inflamed tissue of mammals bytopical, oral, mucosal or parenteral application of a complexcarbohydrate of the present invention or mixture thereof as the onlyactive ingredient. By trauma is meant an event that produces an adverseeffect on a mammal. By sequelae of trauma is meant the pain, swelling,inflammation, adhesion formation, nerve damage, nerve sensitivity andany other physiological change that results from trauma.

[0032] Many of the complex carbohydrates of the present invention aremacromolecules. Macromolecules as used herein means any molecule with amolecular weight >1000 daltons (Da). Mammals as used herein includes butis not limited to humans, dogs, cats, horses, cattle, swine, rabbits,guinea pigs, mice. Topical administration as used herein meansapplication to the dermis anywhere on the mammal, including into the earcanal. Mucosal administration as used herein means application to anymucous membrane of a mammal. Mucous membranes include but are notlimited to the mouth, gums, nasal passage, throat, vagina and therectum. Transdermal as used herein means transfer of molecules,including macromolecules through the skin of mammals so that the complexcarbohydrates may act systemically. Transmucosal as used herein meanstransfer of molecules, including macromolecules through the mucousmembranes of mammals so that the complex carbohydrates may actsystemically.

[0033] Diseases preventable and treatable by the present inventioninclude but are not limited to tonsillitis, the common cold,pancreatitis, ulcerative colitis, stomach or intestinal ulcers, coldsores, Lupus Erythematosis, Parkinson's Disease, osteoarthritis,degenerative arthritis, rheumatoid arthritis, polymyositis, AmyotrophicLateral Sclerosis (ALS) or Lou Gehrig's Disease, multiple sclerosis,Creutzfeldt-Jakob Disease heart disease, heart attack, vasculitis,stroke, Alzheimer's disease, asthma, emphysema, allergy-relateddiseases, Human Immunodeficiency Virus (HIV)disease, yeast infections,bacterial infections, encephalitis, epilepsy, meningitis, peripheralneuropathy, Bell's Palsey, Cerebral Palsey, cancer and Diabetes.Conditions preventable and treatable by the above-described complexcarbohydrates include but are not limited to ulcers, gastritis,esophaqitis, bronchitis, sore throat, tendonitis, fibromyalgia,headaches including migraines, vaginitis, anaphylaxis, hemorrhoids,sunburn, heat burns, temporomandibular joint (TMJ) condition, dentalcaries, dental pain, gingivitis, post surgical pain, menstrual pain,cramps, pre and post partum pain, interstitial cystitis, itchingassociated with allergies and hypersensitivity (poison ivy), painassociated with insect bites or stings, Attention Deficit Disorder,Attention Deficit Hyperactivity Disorder (ADHD), Turret's Syndrome,plaque formation in arteries and veins, degradation of spinal nervespost spinal cord injury, head and brain trauma post injury, adhesionformation post surgery or post chemotherapy treatments, scar formationpost surgery, wound healing, decubutis ulcers, irritation of nervebundles (trigger points) ganglion formation, cognitive disorder, skinproblems such as acne, eczema, lick granulomas, hot spots, psoriasis,rashes, wrinkles, and even hair loss.

[0034] Particularly amenable conditions or diseases targeted for suchprevention or treatment include but are not limited to irritated orinflamed muscles, cramped muscles, inflamed tendons, inflamed nerves ornerve bundles (e.g. inflamed ganglion, lick granulomas, trigger points,fibromyalgia), swollen and painful joints, inflamed bladder(interstitial cystitis) bruised tissue, tired feet, allergic conditionsof the skin, other allergic conditions (e.g. hot spots, psoriasis,asthma, ADD and ADHD), chronic fatigue syndrome, open wounds, decubitisulcers, burns, sunburns, inflamed stomach or intestinal lining(gastritis, colitis, ulcers), dental problems, inflamed bronchi oresophagial lining, adhesions formed after surgery, trauma orchemotherapy, pain post surgery, dental work or injury, plaques formedon veins or arteries leading to heart disease and stroke, inflammationassociated with Alzheimer's Disease, Multiple Sclerosis, amylotropiclateral sclerosis (ALS), head or brain trauma, degration of the spinalcord post spinal cord injury, tumor formation and tumor metastasis.

[0035] A significant advantage of this invention is that pharmaceuticalgrade complex carbohydrates are not required for topical, oral ormucosal application. The invention preferably uses cosmetic or foodgrade (e.g. low purity) complex carbohydrates for these applications.Such complex carbohydrates can be obtained from any source as long asthe source is not contaminated with undesirable adventitious agents(disease-producing viruses, bacteria, fungi, parasites, etc.). Such lowpurity complex carbohydrates such as mucopolysaccharides may becontaminated with up to 20% wt/vol proteins, 15% wt/vol nucleic acids,1% wt/vol teichoic acids, 5% wt/vol lipids, fractions of hyaluronic acid<30,000 (defined as reactive by both Balazs in U.S. Pat. No. 4,141,973and della Valle in U.S. Pat. No. 5,166,331), 5% wt/vol endotoxins andother small molecules They will cause reactions when injected intomonkey eyes or joints of horses but will not cause reactions whenapplied to the skin of mammals or when delivered orally or mucosally tosuch mammals. Because the low purity pharmaceutical compositions of thisinvention are applied topically, orally or mucosally, these contaminantsproduce no adverse reactions (e.g. irritation or blistering of skin).Additionally, if one must select and use only certain molecular weightranges of hyaluronic acid or salts thereof, the cost would beprohibitive. In fact, the presence of multiple molecular weightfractions in compositions of the immediate invention is preferable forefficacy.

[0036] In order to assure freedom from contaminating microorganisms, theformulations of this invention can include preservatives allowable infoods or topical preparations. Allowable preservatives include but arenot limited to methyl and propyl parabens, propylene glycol,ethylenediamine tetraacetic acid (EDTA), sorbitol, ascorbic acid,sorbate and sorbic acid, benzoic acid, and any other acceptablepreservative, including mixtures thereof.

[0037] All molecular weight ranges of complex carbohydrates areeffective in formulations of this invention. For instance, complexcarbohydrates with a molecular weight of <1,000, 1,000 to 30,000,100,000-500,000, >1,000,000 or >4,000,000 have proven to be effective.It has been found that complex carbohydrates, especiallyglycosaminoglycans with lower molecular weights (e.g. <30,000) act morequickly than those with high molecular weights (e.g. >1,000,000).Indeed, for treatment of allergy-related diseases and autoimmunediseases or conditions, it is preferable to administerglycosaminoglycans, especially sodium hyaluronate, salts or derivativesthereof (also called hyaluronic acid or hyaluronan) with a molecularweight average below 300,000 Da. For inflammatory diseases, diseases orconditions related to the adhesion cascade, the metastatic cascade orthe coronary cascade, the high molecular weight glycosaminoglycansprovide a longer-lasting effect. The latter macromolecules are brokendown by enzymes in the body (hyaluronidase) to smaller molecules thatare active in binding or stimulate production of increased amounts oflower molecular weight hyaluronic acid by the mammals' own body.Therefore, there is a longer release of the more active smallermolecules producing a longer period of efficacy. Thus, the preferredformulation for most treatments includes a mixture of low and highmolecular weight complex carbohydrates.

[0038] It has been noted by the inventors that the optimum molecularweight for treatment of allergies, allergy-related diseases andconditions, asthma, ADD and ADHD is between 30,000 and 500,000 Da,preferably between 100,000 and 300,000. It has been determined that veryhigh molecular weight (>4×10⁶) is essentially ineffective for treatmentof the above.

[0039] The complex carbohydrates useful in combination with transdermalor transmucosal carriers for direct topical or mucosal application onsites of trauma or to be absorbed therein, may be of any type alreadyrecognized as useful for parenteral treatment. Additionally, complexcarbohydrates, including polysaccharides, glycosaminoglycans or theirderivatives that bind to leukocyte receptor sites and/or bind toselecting, integrins, or any other receptor sites that are involved withthe mechanisms by which leukocytes move to sites of trauma or thatenable metastasis of tumors and that, when bound, serve to inhibit anyof the steps of the adhesion cascade, allergy or autoimmune mechanisms,the metastatic cascade, or the coronary cascade would be useful in suchpharmaceutical compositions. Such compounds may be obtained from anysource. They can be extracted from rooster combs (U.S. Pat. No.4,141,973), produced by fermentation of bacteria (U.S. Pat. No.4,782,046), or extracted from trachea, skin, umbilical cords, etc. andneed only be pure enough to be used as a cosmetic in that they do notcause reactions when administered topically, orally or mucosally. Thesemolecules include but are not limited to polysaccharides,glycosaminoglycans such as hyaluronic acids and derivatives or saltsthereof (Genzyme, Lifecore Biomedicals, Meiji Seika Kaisha, Ltd.),chondroitin sulfates A, B, or C or their derivatives (SIGMA ChemicalCompany), keratan sulfate and derivatives thereof (SIGMA ChemicalCompany), heparin or heparin sulfate and derivatives thereof (SIGMAChemical Company, Rhone. Poulenc Rorer Pharmaceuticals), dermatansulfate and derivatives thereof (SIGMA Chemical Company) and certainsialylated sugars such as trifucosyllacto-N-hexaose and sialyl Lewis^(x)(Oxford Glycosystems). The sources listed are exemplary only and notlimitations of the invention.

[0040] The preferred complex carbohydrates of this invention aremucopolysaccharides (glycosaminoglycans) including hyaluronic acid andsalts, sulfates or derivatives thereof, chondroitin sulfate andpolysulfated forms, salts or derivatives thereof, sialyl Lewis^(x) andsalts or derivatives thereof, heparin and sulfates, salts or derivativesthereof, dermatan, and sulfates, salts or derivatives thereof, keratinand salts, sulfates and derivatives thereof, as well as combinations ofthe above. The most preferred complex carbohydrates are hyaluronic acidincluding salts, sulfates or derivatives thereof, chondroitin sulfateincluding polysulfated forms, low molecular weight heparin includingsalts, sulfates and derivatives thereof and sialyl Lewis^(x) includingsalts and derivatives thereof and combinations thereof.

[0041] It is a preferred embodiment of this invention that at least twodifferent molecular weight ranges of complex carbohydrates be includedin the composition. At least one should be from a low molecular weightrange {from 1000 to <50,000 (e.g. 49,000)} and the other one or moreshould be from a higher molecular weight range (from 100,000 to 500,000or >1,000,000). Such complex carbohydrates may or may not be a mixtureof two or more different types of complex carbohydrates. For instance,one complex carbohydrate providing the high molecular weight moietycould be selected from the group consisting of glycosaminoglycans suchas hyaluronic acid and another complex carbohydrate in the samepharmaceutical composition providing the low molecular weight moietycould be a second polysaccharide or a sialylated sugar selected from thegroup consisting of chondroitin sulfate, keratan sulfate, heparin,heparin sulfate, dermatan sulfate, acemannan, sialyl Lewis^(x), andhexaoses. When heparin is used, it is advantageous to use low molecularweight heparin as it has been demonstrated to be free of anti-coagulantactivity. However, high molecular weight heparin will be broken down tolow molecular weight heparin when administered orally or mucosally.

[0042] A more preferred embodiment of this invention comprises a mixtureof at least two glycosaminoglycans. One of the glycosaminoglycans wouldbe of a low molecular weight range (<30,000). The secondglycosaminoglycan would be of a high molecular weight (>500,000 Da).

[0043] The most preferred embodiment of this invention comprises amixture of two or more molecular weight ranges of hyaluronic acid orsalts or derivatives thereof, such as sulfates, acetates, phosphates,methylates and nitrates. Said composition comprises for instance, ahyaluronic acid or salt or derivative thereof with a molecular weight of<100,000 Da combined with a hyaluronic acid or salt or derivativethereof which has a molecular weight >1,000,000 Da.

[0044] Routes of administration of the complex carbohydrates of thepresent invention include parenteral (discussed below), topical wherebythe compounds may or may not be combined with transdermal carriersincluding but not limited to essential oils; oral whereby the compoundsmay or may not be mixed with transmucosal carriers including but notlimited to essential oils or other transmucosal carriers, coated withprotective oral delivery materials such as hydrogels, carbopols, etc.,or delivered orally without a coating wherein the complex carbohydratesare the sole active ingredient, mucosally wherein the complexcarbohydrates are the sole active ingredients or parenterally. Forpurposes of this invention, mucosal delivery includes but is not limitedto application of the compounds to the mucous membranes of the nose,eyes, mouth, throat, gums, tonsils, eyes, esophagus, stomach, colon,rectum, vagina, or any other mucous membrane.

[0045] It should be understood that complex carbohydrates used forparenteral administration to mammals must be pure enough to be injectedsafely without causing adverse local or systemic effects and of aviscosity allowing ease of injection. The preferred viscosity is thatwhich is safe to administer without stimulating an adverse effect in amammal. The intravenous route would require a lower viscosity than otherparenteral routes of administration. For instance, a viscosity of 500centipois should not cause problems. A preferred viscosity is less than200 centipois. In the case of parenteral injections, especially thoseadministered IV, pharmaceutical grade complex carbohydrates may benecessary. Parenteral injections may be administered intramuscularly(IM), intravenously IV), subcutaneously (SC), intradermally (ID),intraparitoneally (IP) and/or injected into tumors.

[0046] The parenteral formulation of the present invention may be in anaqueous form as a liquid or gel that is safe when injected IM, SC, IV,ID, IP, or by any other route of administration. This formulation mustbe purer and be of a pharmaceutical grade. By a pharmaceutical grade ismeant that it should be sterile, contain <3% protein (w/w), <5 μg/mLnucleic acids as measured by UV absorbance at 260 nm, <0.5 EU/mLendotoxin as measured by LAL, <80 ppm (w/w) iron and <1.0 ppm heavymetals. The most effective injectable formulation would containmucopolysaccharides or glycosaminoglycans, more specifically, lowmolecular weight heparin, hyaluronic acid of all molecular weights,chondroitin sulfate, dermatan sulfate and/or keratin sulfate. Ifhyaluronic acid is used, the viscosity must be at a level acceptable tobe injected by the route chosen without causing adverse reactions. Forinstance, high viscosity hyaluronic acid >1000 centipoise would not beinjected intravenously whereas it could be injected subcutaneously orintramuscularly. Low viscosity hyaluronic acid <500 centipoise could beinjected intravenously, subcutaneously or intramuscularly.

[0047] Administration of complex carbohydrates by the parenteral routesof administration has been found to be particularly effective in thetreatment of any type of inflammation, pain, nerve damage, nervesensitivity, autoimmunity and/or itching which is associated with theadhesion cascade, tumors associated with the metastatic cascade anddevelopment of heart diseases and stroke associated with the coronarycascade described earlier. This route of administration is preferablefor treatment of pain post surgery or dental procedures, treatment forvarious types of cancer wherein patients cannot ingest food or liquids,treatment of degenerative muscle and joint diseases including thetreatment of Multiple Sclerosis, ALS, osteoarthritis, rheumatoidarthritis, or post partum pain. It is also useful for treatment ofspinal cord injuries, treatment of heart attacks and stroke (e.g. heartdisease due to high blood pressure and stroke), treatment of pain andswelling and/or fractures resulting from athletic injuries, treatment ofinflammation and pain associated with bursitis, reduction ofinflammation (edema) in extremities resulting from diabetes, reductionof inflammation and pain in association with interstitial cystitis,treatment of decubitus ulcers resulting from poor circulation bydiabetic patients or bedridden patients, treatment of inflammation anditching of skin resulting from severe allergic reactions such as poisonivy and insect bites/stings, treatment of sever ADD, ADHD or autism,treatment of anaphylaxis, treatment of polymyositis, treatment ofinflammation and pain associated with tendonitis, treatment ofinflammatory skin conditions such as severe acne or psoriasis andtreatment of burns or sunburn. In severe situations, treatment mayinclude both parenteral injection and oral, mucosal or topicalapplication of one or more complex carbohydrates.

[0048] As indicated earlier, the most recent theories to explain heartattacks and stroke involves the eruption of unstable plaques which havebeen found to be infiltrated with T-cells and macrophages thus linkingthese disease syndromes to the adhesion cascade. Thus, the presentinventors have determined that heart disease (high blood pressure, heartattacks and stroke) can be treated with the complex carbohydrates ofthis invention. Further, hyaluronic acid, chondroitin sulfate, heparinsulfate, low molecular weight heparin, keratin sulfate or dermatansulfate, including salts or derivatives thereof can be taken daily as apreventative for heart disease and stroke. Preferably, amounts from 1mg/day to 20 mg/day are used to prevent heart disease and stroke. Thiscould be administered orally or mucosally. Acute disease, includingheart attacks could be treated by parenteral injection of the complexcarbohydrates of the present invention. Alternately, a mixture ofhyaluronic acid and chondroitin sulfate could be administered daily forprevention of heart disease and stroke. Again, the daily dose wouldpreferably be less than a total of 100 mg. Repeated low doses have beendemonstrated to be between 0.0001 mg and 100 mg.

[0049] For topical, oral and mucosal deliver, transdermal ortransmucosal carriers can be added to enhance the penetration of thecomplex carbohydrates through the skin or mucous membranes. Transdermaland transmucosal carriers include but are not limited to essential oils,polymer blends containing low density polyethylene copolymer or ethyleneand 1-butene, 1-hexene, or 1-octene and a linear low densitypolyethylene copolymer, chemical esters, salicylates, dimethyl sulfoxide(DMSO) and glycocholates. It is preferred that very low concentrationsof essential oils be used to orally or mucosally deliver the complexcarbohydrates of the present invention, including the macromolecules,through mucous membranes and, consequently, into the blood stream. Byvery low concentration of essential oils for use in mucosal orparenteral administration is meant that the essential oil is added to aconcentration in an amount from 0.00001% to no more than 1%, preferably,no more than 0.01%, more preferably no more than 0.005%. Therefore,concentrations of essential oils around 0.00001% and 0.005% arepreferred for transmucosal delivery.

[0050] Transdermal formulations of the present invention utilizeslightly higher concentrations of essential oils. These range from 0.05%to 5.0%, preferably from 0.5% to 3.0%.

[0051] The essential oils of the present invention may be either naturalor synthetic and may be obtained from any source. For instance, naturalEucalyptus Oil, Rosemary Oil, Pine Needle Oil, Tea Tree Oil, Sage Oil,Jojoba Oil, Cinnamon Oil, Anise Oil, Lemon Oil, Lime Oil, Orange Oil,Peppermint Oil, Spearmint Oil, Wintergreen Oil, Clove Leaf Oil, AlmondOil, White Pine Oil, Camphor Oil, Cardamon Oil, Cedar Leaf Oil, SweetBirch Oil and many others can be purchased from Lorrann Oils. SyntheticWintergreen Oil, Anise Oil, Fir Tree Oil, Rose Oil and Camphor Oil canbe obtained from the same source. Menthol and derivatives thereof can beobtained from SIGMA Chemical Company. The purity of these essential oilsis of little concern as long as they meet the requirements for a food orcosmetic and do not produce adverse reactions when applied to the skinof mammals. An example of an animal-derived essential oil is EMU oil,extracted from the skin of the EMU.

[0052] The formulation of a complex carbohydrate with a natural orsynthetic essential oil should be adequate to form an emulsion,suspension, solution, cream or ointment at the time of application. Aliquid formulation will not be effective if the oil is separated fromthe aqueous phase. However, a suspension or solution that may beresuspended by shaking prior to application is acceptable for use. Anycream or ointment base that does not interfere with the effectiveness ofthe active ingredients may be included in the formulation. Therefore,one embodiment of this invention is a cream base containing at least onecomplex carbohydrate and at least one essential oil. Another embodimentis an ointment base containing at least one complex carbohydrate and atleast one essential oil. One preferred embodiment is a liquid or gelformulation in an aqueous base that contains at least one complexcarbohydrate and at least one essential oil. A significant advantage ofthis liquid formulation is that the preparation is not greasy or oily,does not leave a greasy or oily film on the skin and does not leave alingering odor on the skin. The most preferred embodiment is a liquid orgel formulation in an aqueous base that contains at least one complexcarbohydrate as the sole active ingredient.

[0053] The complex carbohydrates of the present invention can also beprepared as a solid and incorporated into bandages. Preferably a 1%solution is used. It can be embedded into the bandage material remainingmoist, or dried. It can also be formulated into a solid polymer byaddition of cross-linking agents. The latter may be applied to openwounds or to scars to assist with the healing process and/or reduce scarformation.

[0054] The treatment of irritated or inflamed mammalian tissue by directtopical application requires a dose or total dose regimen effective toreduce or alleviate the results of the trauma. It is preferred toadminister at least about 0.000001 mg/Kg of body weight of eachingredient over the site of trauma at least once per day or as often asnecessary. The components of this formulation are naturally-occurringsubstances and are safe when applied topically. There is no inherentupper limit to the tolerable dose. However, as in all medicinaltreatments it is prudent to use no more than is necessary to achieve thedesired effect. It has been noted that more intense inflammation andpain require more dose applications for relief. A dose of 100 mg/Kg ofbody weight has been used safely and could serve as an upper limit foruse. Similar dose regimens are recommended for wound healing whereas thepharmaceutical composition is applied on the wound until adequatepromotion of granulation of the wound has occurred and healing iscomplete.

[0055] A convenient topical application formulation is a combination ofone or more complex carbohydrates such as polysaccharides,oligosaccharides, or glycosaminoglycans at a total concentration ofbetween 0.1% and 5% wt/vol. These can be used without a transdermalcarrier or with a transdermal carrier including one or more essentialoils. If essential oils are used, they are preferably combined with thecomplex carbohydrates at a total concentration of between 0.5% and 20%vol/vol with the remainder of the formulation being made up of a liquid,cream or ointment base. The liquid base may be aqueous.

[0056] A preferred embodiment of the topical formulation is acombination of one or more glycosaminoglycans at a total concentrationof between 0.1% and 5% wt/vol with one or more essential oils at a totalconcentration of between 0.5% and 5% vol/vol with the remainder of theformulation being a cream, ointment or aqueous base.

[0057] A more preferred embodiment of the invention is a combination ofequal amounts of two or more molecular weight ranges ofglycosaminoglycans(one below 30,000 and one above 500,000) at a combinedconcentration of between 0.5% and 3.0% wt/vol with two or more essentialoils having a total concentration of between 0.5% and 5.0% vol/vol withthe remainder of the formulation being an aqueous, cream or ointmentbase.

[0058] The most preferred embodiment of the topical formulation is acombination of hyaluronic acid (sodium hyaluronate or hyaluronan) with amolecular weight <30, 000 with hyaluronic acid with a molecular weightbetween 100,000 and 500,000 or >750,000 at a total hyaluronic acidconcentration of between 0.5% and 3.0% wt/vol and an essential oilselected from the group comprising Rosemary Oil, Tea Tree Oil,Wintergreen Oil, Eucalyptus Oil, Menthol and Camphor at a concentrationof between 1.0% and 3.0% vol/vol with the remainder of the formulationbeing DI water.

[0059] Preferred complex carbohydrates include heparin, preferably lowmolecular weight, hyaluronic acid, chondroitin sulfate, dermatansulfate, keratan sulfate, and acemannan (active ingredient of AloeVera).

[0060] Preferred essential oils include Tea Tree Oil, Rosemary Oil,Eucalyptus Oil, Wintergreen Oil, Sage Oil, Jojoba Oil, White Pine Oil,Camphor Oil, Cinnamon oil, Oil of Clove, Spearmint Oil, Peppermint Oil,EMU Oil and Menthol.

[0061] The oral and mucosal formulations of the present inventioninclude any of the complex carbohydrates listed above, alone or incombinations, whereby the formulation is administered as a form selectedfrom the group consisting of a liquid, an emulsion, a suspension, acream, an ointment, a gel, a foam, a spray, a solid, a powder and a gum.It is contemplated that the liquid or solid could be added to a drink ordrink mix, to food, be a part of a soft drink or any other type ofcarbonated drink, a supplement drink, used as a mouthwash, or added to amouthwash, as a toothpaste, as a gargle, as a spray, added to avaporizer, as a liquid center of a gum or throat lozenge, added to afood, cookie or treat, or used in any other way so as to retain theeffectiveness of the complex carbohydrate. A gel form can include a gelapplied by mouth, to the gums, to the tongue, under the tongue, to theeyes, to the nose, to the vaginal area or vagina, or to the rectum. Afoam could be added to wounds, to the mouth, to the gums, to the vaginaor any other mucous membrane. A solid can be incorporated into food,treats such as candy or treats for animals, a chewing gum, a dissolvablegum, a lozenge, capsules, tablets, dissolvable tablets, suppositories, abandage and any other form that would not damage the effectiveness ofthe complex carbohydrates or the essential oils, if used in theformulation. Other additives may be added to said oral formulations toimprove taste and palatability or enhance the flavor. For instance,treats for horses may include sugar, flavorings such as apple orpeppermint or a liquid or gel may be applied to a sugar cube, food orother treat. Treats for dogs may include liver, apple, peppermint, yeastor any other palatable flavoring.

[0062] The same formulations as mentioned for oral use can be used formucosal delivery of the complex carbohydrates. The only limitation isthat the formulation remain in contact with a mucosal surface for aperiod of at least 2 to 10 seconds.

[0063] Although the complex carbohydrates may be added to foods that arethen baled, it is preferred to add the complex carbohydrates to thesurface of the food after baking is complete. This retains the greatestactivity.

[0064] It is contemplated that the complex carbohydrates of the presentinvention may be added to nutritional supplements to enhance theireffectiveness. For instance, a mixture of complex carbohydrates andzinc, zinc gluconate, zinc gluconate glycine could be used for moreeffective treatment of sore throat and colds. A mixture of the complexcarbohydrates of this invention and capsicum may produce an even moreeffective treatment for joint pain and swelling. Addition of vitamins,minerals and other nutritional additives may produce enhancement of thenutritional activity by the complex carbohydrates.

[0065] The most recent theory to explain the significant neurologicaldegeneration that occurs in Alzheimer's Disease involves a substantialinflammatory component (SCIENCE, vol: 286, Dec. 17, 1999, pgs 2352-2355)which appears to be related to the Adhesion cascade. Therefore, thepresent inventors have determined that the complex carbohydrates of thisinvention can be used to prevent and/or treat Alzheimer's Disease. Forexample, it is contemplated that hyaluronic acid, salts or derivativesthereof could be administered daily as a preventative for Alzheimer'sDisease. Amounts from 1 mg/day to 20 mg/day should prevent thedegradation apparent in Alzheimer's Disease. This could be taken orally.Preferably, it would be taken mucosally. Acute Alzheimer's Disease couldbe treated by parenteral injection. Alternately, a mixture of hyaluronicacid and chondroitin sulfate could be administered daily for preventionor treatment of Alzheimer's Disease. Again, the daily dose wouldpreferably be less than a total of 100 mg.

[0066] The significant neurological degeneration that occurs afterspinal cord injuries leading to irreparable paralysis, is attack by theleukocytes rushing to the site of trauma (via the mechanism of theadhesion cascade) to help repair the traumatized area, but instead,degrading the ends of the nerves in the spinal cord, fraying them whicheffectively inhibits their potential realignment and partial or completerepair. Paralysis resulting from spinal cord injuries may be preventedor treated effectively using the complex carbohydrates of thisinvention. In this case, since the patient may not be able to take anoral medication, the medication may be administered mucosally usingsuppositories (rectal or vaginal) or parenterally, injecting IM, SC, ordelivering IV. The dose may need to be higher, in the range of 20 to1,000 mg per day. Drugs to assist repair of nerves would preferably beadministered concurrently.

[0067] The invention is further illustrated but is not intended to belimited by the following examples.

EXAMPLE 1

[0068] An 18 year old female suffered from chronic fibromyalgialocalized in the face and neck. This condition had existed forapproximately 5 years. There was nothing that provided relief for hercondition. Prior to use of the compositions of the present invention,she had taken pain relievers, acupuncture, and numerous other proceduresto treat her condition. Nothing had provided substantial relief withoutsevere side effects. She was given a formulation containing a mixture ofhigh and low molecular weight 1% sodium hyaluronate. This formulationwas prepared from hyaluronic acid powder obtained from CollaborativeLaboratories, Inc. which was made up to a 1% solution in deionized,distilled water. One half of the final 1% solution was removed and itsmolecular weight was broken down by alkaline hydrolysis. The pH wasadjusted to between 11 and 14 using 10N NaOH. Then the solution washeated while mixing at a temperature between 37° and 50° C. When amolecular weight of between 10,000 and 50,000 was obtained as measuredby viscosity (Brookfield Viscometer), the pH was adjusted back toneutral (between 6.0 and 7.0). The final mixture was then prepared bycombining 1 liter of this low molecular weight preparation with 1 literof the original 1% solution (high molecular weight of >1×10⁶) of sodiumhyaluronate. The patient was instructed to take this formulation orally,holding the liquid in the mouth for several seconds to allow mucosaladsorption before swallowing it. She took 10 mg two times per day (AMand PM). This represented a dose of approximately 0.2 mg/Kg. Shereported that after only 1 day, her symptoms were greatly improved.After one week of daily use, she reported essentially no pain. She hascontinued to take the same dose for 6 months and has reported no returnof her fibromyalgia as long as she takes the formulation. Therefore, acondition that has historically remained untreatable, and which appearsto be related to the adhesion cascade and, perhaps, to allergies hasbeen shown to be treatable with the compositions of the presentinvention.

EXAMPLE 2

[0069] A 9 year old male suffering from severe Attention DeficitHyperactivity Disorder (ADHD) complicated by Turret's Syndrome, who wasbeing treated by diet control with little success, was given a sample ofthe mixture used in EXAMPLE 1. This treatment was not complicated byconcurrent treatment with drugs such as Ritalin as his parents wereadverse to using this medication. Therefore, any response observed wasrelated to the use of the complex carbohydrates of the presentinvention. He took 10 mg in the morning and 10 mg in the evening, usingthe solution as a outhwash (holding it in his mouth for about 10 to 20seconds and then swallowing). His parents kept very strict records ofhis activity and noted that his Turret's Syndrome was fully controlledand he suffered no tics while taking the sodium hyaluronate. The one daythat he forgot to take his morning dose he had a recurrence of his ticsand became almost uncontrollable. However, within 15 minutes of hisreceiving the missing dose, he became calm and returned to normal. Thisboy has remained totally under control for 6 months. This had never beenobserved before, even when he was taking Ritalin. He had discontinuedtaking Ritalin 1.5 year before because of problems with side effects.The sodium hyaluronate provided no adverse reactions or side effects. Ithas been concluded that a disease typically thought to be related to anervous disorder or to allergies was treatable by the complexcarbohydrates of the present invention.

EXAMPLE 3

[0070] A 60 year old male and 55 year old female (brother and sister)who routinely suffered severe sunburns the first few times that theywere in the sun each summer, had been taking oral sodium hyaluronate gelfor treatment of pain associated with a cervical disc stenosis (male)and chronic osteoarthritis of both knees (female). Pain from theconditions being treated was totally controlled by taking 5-10 mg twiceper day. This dose represented 0.14 and 0.18 mg/Kg respectively. Thesodium hyaluronate gel was prepared by adding sodium hyaluronate(Collaborative Laboratories, Inc) to deionized, distilled water to a 1%concentration. Preservatives selected from methyl paraben (0.17%),propylparaben (0.025%) and propylene glycol (10%) were added to maintainsterility of the liquid preparation. The pH of this preparation wasbetween 6 and 8 and the preparation had a molecular weightof >1,000,000. The gel was being applied directly on the tongue bydropper bottle. Both went on vacation together and spent most of 5 daysin the bright sun in a boat. They did not use a sun blocker. Eachprevious year both had suffered severe discomfort from sunburn after thefirst day's exposure. This time, at the end of the 5 days, both notedthat they were not sunburned, had suffered no discomfort and weredeveloping a nice tan. It is concluded that the preparation of thisinvention prevented sunburn, allowing tanning to occur. Additionally, itwas noted that the formulation of this invention was able to control thepain associated with cervical disc degeneration and osteoarthritis. Allsuch conditions are associated with the adhesion cascade, confirmingthat diseases and conditions associated therewith are preventable ortreatable by the complex carbohydrates of the present invention.

EXAMPLE 4

[0071] A 60 year old male suffering from colon cancer had been unable totolerate his colostomy and demanded that his surgeon remove thecolostomy and reconnect his colon. He refused chemotherapy. He was givena formulation of 1% sodium hyaluronate (Collaborative Laboratories, Inc)which was prepared with a mixture of molecular weights of hyaluronate(as described in EXAMPLE 1). When he began taking the hyaluronatepreparation, his CEA was 70.1. He has taken the hyaluronate at a dose of10 mg three times per day mucosally and after 6 months of treatment hisCEA has dropped to 4.1. He has taken no other treatments. This patienthad also suffered from polymyositis for approximately 15 years. For thiscondition he was taking 50 mg of Prednisone daily with little relief. Hereported that after 1 week of taking the hyaluronate preparation of thepresent invention, he felt significant relief from the pain caused byhis polymyositis. After 6 months of treatment with hyaluronate, he hasbeen able to reduce his Prednisone to 5 mg every other day. Hisphysician has reported that his polymyositis has gone into remission.This treatment of cancer demonstrates the successful use of the complexcarbohydrates of the present invention to treat a disease associatedwith the metatastic cascade. The polymyositis that was successfullytreated in this example was thought to represent treatment of a diseaseassociated with the adhesion cascade or autoimmune disease.

EXAMPLE 5

[0072] The subject adult was a 48 year old female who had suffered allher life with attention deficit disorder (ADD). She never knew what herproblem was until recently when she was diagnosed. She described herchildhood as unfocused and explained that she felt as though she was ina constant mental fog—unable to think clearly, or for that matter,unable to focus on a thought at all. She found that she had allergies toalmost everything including most foods (dairy products, wheat and corn,sugar, corn syrup, etc.) and most environmental inhalants, the worstbeing mold. Exposure to only a few minutes in a moldy room caused thisindividual to become dazed, unable to think, focus or even stay awake.She had only been able to do menial jobs. She spent most of her timestaring out the window with no thoughts in her mind and, even if shetried, could not focus on a thought or task. She described herself asbelieving all her life that she was just stupid and unable to learn. Shehad been to multiple physicians and psychiatrists seeking treatment withno success. She had taken Ritalin with little relief. It allowed her tofunction partially but she was always tired and unable to focus onanything but the simplest of tasks. She agreed to take the oral sodiumhyaluronate product and her family would report how she reacted. She didnot believe that she could record her own responses because she wasunable to concentrate long enough for such a task. She was initiallyprovided low molecular weight sodium hyaluronate (<30,000), prepared asdescribed in EXAMPLE 1. She began by taking 20 mg 3 to 4 times per day.Within five days of the start of treatment, she reported that she couldfocus enough to write a note about how she felt each day. As she was onthe instant composition longer, her notes became more coherent andwithin about 10 days she was able to determine exactly which foodscaused her the most problems and which environmental exposures causedthe major difficulty. She discovered that various types of foods wereactually producing her “mental fog” reaction, an anger reaction, weltson her face and neck and even anaphylaxis. After 30 days of taking thesodium hyaluronate oral formulation, she described her response asfollows: “Before starting the oral formulation, I was in a continualstate of feeling tired, foggy, feeling cold, having rashes and welts allover, and having a ‘tight head’. I couldn't function well enough todrive or hold any type of job. I now believe that I know what a normalperson must feel like. I'm having longer periods of well being, energyand clear thinking. Each week I have seen a progression of positiveresponses. This is the first time I have been able to define periods ofallergic reaction. I can observe when reactions start and end. I'm notusing nasal spray (Flonase) in the morning when I wake up or, especiallybefore I go to bed. Before starting the oral formulation, I had to usethis spray before bedtime or I would wake up in the middle of the night,coughing and choking with a lot of phlegm. I am able to start and finishprojects. I have even been able to work crossword puzzles—something thatI could never even look at prior to treatment. My quality of life is farsuperior than ever before. I have been offered a real job at anadvertising agency. I feel like I can handle the Job and do not getfrustrated and spacey. I am also able to drive a car—something that Ihaven't done for at least 15 years.”

[0073]FIG. 1 plots the response of this patient while taking thecompositions of the present invention. It is based on the patient's owndescription of her average daily activities and reactions. The scaleruns from a −30 (a reaction in which the patient responded in a mannerwherein she was unable to function or focus on any activity) to +30(energy, clear-thinking, able to focus, feel great). If there were nosignificant negative or positive responses during a day, the reactionrate was recorded as 0. The graph clearly demonstrates that the oralglycosaminoglycan (sodium hyaluronate) improved this patient's qualityof life and reduced the reactions (after eating or exposure toenvironmental reactants). Toward the latter part of treatment, thispatient was provided with a high molecular weight (>1,000.000) oralhyaluronate formulation. Her family reported an immediate lack ofresponse that continued during the time when she continued to take thisformulation. She was unable to work or drive a car during this period oftime. After 9 days on the high molecular weight formulation she wasswitched to a formulation that contained a mixture of molecular weightsof hyaluronate (as described in EXAMPLE 1). This formulation wasprepared by mixing 3 parts of low molecular weight (<30,000) with 1 partof high molecular weight (>1,000,000). She demonstrated an immediatepositive response that has continued. She has reported that whereaswhile taking the low molecular weight hyaluronate she felt extremelyenergetic and capable of doing anything and everything, when she ate orwas exposed to something that caused her significant problems, shesuffered from extreme “crashes”. These “crashes” were observed by theinventor and would be described as a catatonic state in which thispatient did not respond. She sat and stared into space or fell asleep.While taking the mixed molecular weight hyaluronate, she was notexperiencing “highs” or “crashes”. Instead, she maintained a feeling offocus, felt good and was capable of completing her work and family tasksas she thought a normal person would do. As can be observed in the graphin FIG. 1, when the low molecular weight sodium hyaluronate was replacedwith high molecular weight sodium hyaluronate (without the patient'sknowledge) the patient reported a total lack of efficacy. When she wasplaced back on the mixed molecular weight preparation, she returned to astate where she was functioning well, had excess energy and was able tofocus. This individual has now periodically replaced the sodiumhyaluronate with liquid 5% chondroitin sulfate. The positive responsecontinued while taking this low dose chondroitin sulfate.

EXAMPLE 6

[0074] The patient from EXAMPLE 5 did experience 2 anaphylacticreactions after eating certain foods containing corn syrup or beingexposed to mold. During such reactions she would become catatonic andcollapse. After the first such reaction, a pharmaceutical grade lowmolecular weight sodium hyaluronate (approximately 350,000 MW) wasadministered intramuscularly. She was observed for her response. Within10 minutes she became conscious and was able to speak haltingly. She wasunable to focus well on the conversation. Within 30 minutes she appearednormal and was able to carry on a coherent, intelligent conversation.She had no idea what had happened.

[0075] When a similar anaphylactic reaction occurred at a later date, itwas decided to treat with oral hyaluronate. She again was catatonic andunconscious. Approximately 1 mL of low molecular weight (<30,000) sodiumhyaluronate was applied under her tongue and around her gums. Thistreatment brought an initial response of consciousness within 30minutes. Halting speech without the ability to focus occurred by 45minutes post treatment. By 60 minutes post treatment she was able tocarry on a focused conversation and appeared normal. This demonstratesthat a glycosaminoglycan such as hyaluronate can be used to treatanaphylaxis when administered either parenterally or orally/mucosally.

EXAMPLE 7

[0076] The subject child was a 9 year old male who has suffered withADHD all his life. He had demonstrated learning disabilities compoundedwith behavioral problems. He was described as unable to focus, did notread, write or draw. Additionally, his behavior was such that he couldnot socialize with other children or with adults. When in contact withother children he was unable to play, often became angered and causedphysical harm to others. He had been under treatment by severalphysicians, psychologists and allergists all his life but none were ableto help his condition. The allergists determined that he had allergiesto most all foods, dust, molds, soaps and just about everything in hisenvironment. At one time he was prescribed Ritalin daily. However, whiletaking this drug he suffered hallucinations and became even moreuncontrollable. At the time that he began treatment according to thepresent invention, the physician who was treating him was convinced thathis ADHD was related to his severe allergies. Eating a certain food,such as corn, immediately produced anger and rage in this child. Similarresponses were noted after eating or being exposed to other foods ormold.

[0077] This boy attended a special school in which his Teachers reportedhis daily activity to his parents so that they could try to monitor hiseating habits. They provided a daily numerical score. A score of 100 wasexcellent. This child averaged daily scores of 0 to 10, at best. Thischild was placed on the low molecular weight oral glycosaminoglycan,sodium hyaluronate. A dose of 20-30 mg BID was applied orally in food ordrinks. It was added to rice milk for breakfast and made into icing forcookies for snacks as he was not cooperative enough to take it on hisown. His response was monitored by using the numerical score provided byhis teachers and averaging it with a numerical score of his behavior athome provided by his parents. The child responded positively within afew days. The average scores plotted in FIG. 2, ranged from −40 to +40.Normal non-aggressive behavior was given a score of 0. The teachers atschool were not informed of this treatment. Within 5 days of beginningtreatment the comments from his teachers were: “He appears happy, havinga good time but needs direction. Awesome day. Plays well withclassmates. Helps other children who are having problems”. His parentshave commented that he has awakened in the morning and is happy,cheerful and cooperative in getting ready for school. This is somethingthat they had not experienced in the past. He has suffered no adversereactions from taking the complex carbohydrates of the presentinvention. FIG. 2 shows the response of this child to oral low molecularweight hyaluronic acid. The y axis is a numerical analysis of thischild's ability to cooperate with other children and adults. If hisbehavior was belligerent, bossy, angry or non-cooperative he was scoredas a −40 for the day. If his reactions to foods or environmental stimuliproduced such a response it was recorded as a −40. If he responded as anormal 9 year old, the score was recorded as 0. If he respondedextraordinarily well, helping other children, reading quietly, drawingor writing, he was given a score of +40. It was quite surprising thatthis child responded almost immediately becoming “a different child”.His parents had thought that he did not know how to read, write or draw.Almost automatically, he requested books from the library and beganreading quietly, he began drawing very intricate drawings and writingpoems and stories. He also began preparing very elaborate meals for hisparents (without any assistance). FIG. 2 demonstrates this superiorbehavior quite well. It also demonstrates that when treatment wasstopped for approximately 2 weeks, there was a reversion to his originalnon-cooperative behavior. Upon restarting the treatment his behaviorimproved dramatically. It is thus clear that the glycosaminoglycans ofthe present invention can treat ADHD very effectively. Any route ofadministration may produce similar effects In the most severe cases, thetreatment would begin with a parenteral injection followed by oral ormucosal daily doses.

EXAMPLE 8

[0078] 35 The patient was a 37 year old female who had suffered frominterstitial cystitis for eight years. She had seen any doctors and beento Mayo Clinic to seek treatment that could provide her with relief.This condition presents as a constant pain in the bladder that produces“excruciating pain” and a sensation of an intense need to urinate(urgency). It appears to be caused by inflammation of the lining of thebladder. Cysts or sores develop that are irritated by the urine in thebladder. Since the bladder cannot empty, there is constant irritationand constant pain. A recent theory is that the irritation is produced byallergic reactions to certain foods or drinks and by sexual intercourse.This patient had been to all types of physicians and even to the MayoClinic to obtain relief from her pain. She had been taking 100 mg perday of macrodantin and 20 mg per day of feldene that caused severe sideeffects. Additionally, she had taken 200 mg TID of Elmiron to reduce theinflammation in the bladder lining. This did not help. In order to sleepshe took Prosed/DS, Ultram, Hydroxyzine HCl, Cardura, Amitriptyline.Sometimes all were taken at some time during the day or night. Even thisregimen was unable to treat the pain. This patient was supplied with themixed molecular weight preparation of sodium hyaluronate as described inEXAMPLE 1. She was also supplied with a topical preparation containing1% wt/vol. Sodium hyaluronate at a molecular weight of <30,000 combinedwith 1% Oil of Wintergreen, 0.5% Spearmint Oil and 0.2% Peppermint Oil.She took 10 mg of the oral preparation 4 times per day. The last dosewas taken before going to bed. Additionally, at bedtime, she rubbed herlower abdomen (over the bladder) with the topical preparation. Shereported that she was able to sleep at least 6-7 hours without pain andwithout the need to get up to urinate. Within a week after starting thistreatment she was able to discontinue all other medications. Now, allshe requires is 1-2 Tylenol plus the sodium hyaluronate preparation ofthe present invention and she has continued to remain pain free. Thisdemonstrates that inflammation, even in the bladder where the sodiumhyaluronate does not penetrate, can be successfully treated with thecompositions of the present invention. The additional fact that thetopical preparation provided “an extra bonus of immediate relief”indicates that the topical use of the compositions of the presentinvention are extremely effective in treating extreme pain. It isproposed that the allergic reactions that stimulate this condition weresuccessfully treated to relieve the constant irritation of the bladder

EXAMPLE 9

[0079] A 49 year old female who was diagnosed with Lupus Erythematosis24 years ago, presented with an acute outbreak of the disease. Her facewas covered with eruptions as was the skin on her forearms. She was alsofeeling very tired and complained of general joint pain. She wasprovided with a sodium hyaluronate preparation with a molecular weightof <30,000. She was instructed to initially take 10 to 20 mg of theliquid TID. She reported that after taking the first dose, the eruptionson her face began “drying up”. By the third dose the eruptions weresignificantly reduced and beginning to heal. Within 3 days, theeruptions had essentially disappeared. This patient has been treatedwith the composition of the present invention for a period of 8 monthswithout a recrudescence of the disease. She also reported that theconstant aching and pain in her joints had disappeared and she felt 100%improvement.

[0080] Lupus Erythematosis is known to be an autoimmune disease.Therefore, the complex carbohydrate compositions of the present are ableto successfully treat said autoimmune disease.

EXAMPLE 10

[0081] An 80 years old female had been diagnosed with ovarian cancerthat had spread to the lungs, liver and spleen. She refusedchemotherapy. She was told that she had 3 weeks at most to live. She wasprovided treatment with the complex carbohydrate compositions of thepresent invention. When first provided with oral/mucosal sodiumhyaluronate of mixed molecular weights (prepared according to themethods described in EXAMPLE 1), she had not eaten in 6 months and wasunable to keep anything down, she was in extreme discomfort fromextensive build up of fluids in the abdomen and chest and pain in thelegs and feet which were extremely swollen. She was on an IV solution torestore fluids since she could not drink liquids. She was instructed toplace as much as possible of the oral preparation in her mouth and letit absorb under her tongue. This was to be repeated as often aspossible. Within 2 weeks she was able to eat small amounts of food. Atthis time, she received injections of 10 mg doses of sodium hyaluronatethree times per week. Her condition continued to improve. As of thiswriting, she continues to improve, eats better each day and has survivedfor 4 months. She has received no chemotherapy and no other treatments.She indicates that she feels stronger each day and has been able tobegin sitting in a chair and standing up. She has indicated that she hasno pain since beginning to take the oral complex carbohydrates of thepresent invention. This demonstrates that even a terminal cancer patientwho was near death can respond to treatment with the complexcarbohydrate compositions of the present invention.

EXAMPLE 11

[0082] A 38 year old male had suffered from high blood pressure most ofhis adult life. He had tried taking numerous drugs to treat hiscondition with little to no success. He agreed to try a complexcarbohydrate of this invention to determine whether it might have apositive effect. He was supplied with a 1% solution of sodiumhyaluronate formulation with a molecular weight range between 10,000 and50,000. He took 10 mg in the morning and 10 mg in the evening Sometimeshe supplemented with a 10 mg dose after lunch if he was having aparticularly stressful day. The patient's weight was 163 lbs. Therefore,each dose was 0.06 mg/Kg. Table 1 shows the results. The patient's bloodpressure ranged around 160/115 prior to treatment. Within three days ofstarting treatment his blood pressure was dropping. By one week postinitiation of treatment, his blood pressure was within the normal range.It has remained well within the normal range for six months duringtreatment with the complex carbohydrates of this invention. It isevident that high blood pressure can be effectively treated with thecomplex carbohydrate formulations of the present invention. TABLE 1Treatment of High Blood Pressure with Sodium Hyaluronate BP Prior BP 5min BP 1 hours BP 2 hours to Post post post Day medication medicationmedication medication −3 168/121 N/A N/A N/A −2 166/119 N/A N/A N/A −1169/121 N/A N/A N/A 0 167/119 N/A N/A N/A 1 166/114 160/100 142/98140/88 2 160/100 154/110 150/104 141/89 3 158/90 154/100 143/89 144/89 4148/98 144/99 140/89 139/85 5 149/99 143/87 140/80 139/78 6 150/87145/89 139/85 138/77 7 146/86 144/89 135/78 136/79 8 139/78 136/87135/78 139/81 9 135/85 136/76 133/79 139/78 10 138/87 133/77 134/77133/78 11 137/76 139/88 138/79 141/87 12 137/88 137/89 134/80 135/77 13136/77 136/78 133/76 134/75 14 137/79 134/81 133/75 133/75 15 138/77133/76 132/78 135/74 16 133/74 133/77 134/77 132/68 17 140/78 139/76133/76 133/77 18 133/76  8/78  32/75 133/78 19 135/75 131/73 131/75133/74 20 133/76 131/74 133/73 132/76 30 134/74 135/76 134/71 135/74 180133/78 135/78 136/73 133/72

EXAMPLE 12

[0083] An eleven year old Labrador retriever had suffered from lickgranulomas for at least 3 years. This condition of dogs are reportedlycaused by nervousness wherein the dog continues to lick a certain siteuntil an open wound is produced. Licking is continued and the open woundbecomes significantly irritated and swollen. This dog's granuloma waslocated on the left hind leg above the pasturn. The swelling around theleg measured 8 inches in diameter and the open wound measured 4×3inches. The dog had been treated with cortisone injections andhydrocortisone creams with little success. This dog was injected with 10mg of sodium hyaluronate having a molecular weight ranging from 30,000to 400,000 (1.0 mL intramuscularly—equivalent to 10 mg). The open woundbegan to heal. This injection was followed up with topical applicationof a low molecular weight hyaluronic acid prepared by making a 1%(wt/vol) solution of hyaluronic acid (Medex Ltd) containing 1%Wintergreen Oil (Loranne Oil), 1% Spearmint Oil (Loranne Oil) and 0.5%Peppermint Oil (Loranne Oil). The topical formulation was applied atleast two times per day. Over a period of 2 months the lick granulomahealed completely and the swelling reduced to a diameter of 3 inches.The dog has not licked this area since treatment began. Therefore, thecomplex carbohydrates of the present invention are able to successfullytreat lick granulomas (a previously untreatable condition of dogs) andeliminate the cause of the licking.

EXAMPLE 13

[0084] Dogs often develop areas on their skin that become irritated andthat they lick until the area is raw and oozing. Often these areasbecome infected with normal flora (bacteria) on the skin. Additionally,the hair around the area is usually either licked off or sloughs off.These areas are termed “hot spots”. They are extremely difficult totreat and are thought to be caused by allergies to foods orenvironmental stimuli. Treatment generally includes cortisone byinjection or by mouth followed by antibiotics (oral or topical) to treatthe complication of bacterial infection. Three dogs with severe hotspots were treated with the complex carbohydrates of the presentinvention. Dog #1 had a large hot spot on the top of the head (diameter3×2 inches) and smaller ones around the muzzle area. Dog #2 had a largehot spot on its back just in front of the tail. This area measuredapproximately 6 inches in diameter. Dog #3 had hot spots down the backof both hind legs and on the groin area of both hind legs. Parenteralsodium hyaluronate was administered to Dog #1. This dog received 3×10 mgdoses at one week intervals. The hot spot on dog #2 was treated withtopical sodium hyaluronate. The formulation was the same as thatdescribed in EXAMPLE 15. The topical formulation was applied BIDdirectly on the hot spot. Dog #3 received sodium hyaluronateadministered orally. This dog received 5 mg BID on its food.

[0085] Hot Spots: Reports on the treatment progress were made by theowners and are shown in Table 2. Table 2 indicates that all of thetreatments were effective. It appears that the paternally administeredsodium hyaluronate was slightly more effective than the orally ortopically administered product. However, all were more effective thanthe previous treatments used. Additionally, none of the dogs have hadrecurrent hot spots, even one year after the initial treatment. TABLE 2Response of Dogs with Hot Spots to Treatment with Sodium HyaluronateDays Post Treatment Initiation Dog #1 Dog #2 Dog #3 1 NC NC NC 2 DogQuit Licking NC Dog Quit Licking 3 Drying Dog Quit Licking Drying 4 SameSame Same 5 Healing Well Drying Healing Well 6 Same Same Same 7 SameSame Same 8 Significantly Healing Well Significantly improved Improved 9Same Same Same 10 Same Significantly Same Improved 11 Size now 1 inchSame Same in diameter 12 Same Size now 2 Size now 1 inch inches in indiameter diameter 13 Essentially Same Same healed 14 Same Size now 1inch Essentially in diameter healed 15 Hair growing Essentially Hairgrowing back healed back 16 Hair growing Hair growing Hair growing backback back 17 Same Same Same 18 Same same Same 19 Same Same Same 20Completely Can still see a Hair almost healed slight lesion grown back21 No new lesions Same Same 22 Same Completely Completely healed healed23 Same Same Same 24 Same Same Same 25 Same Same Same 26 Same Same Same27 Same Same Same 28 Same Same Same 29 Same Same Same

EXAMPLE 14

[0086] An 83 year old female suffered from chronic eczema—scaly and redareas on her neck and arms She had also been diagnosed with a yeastinfection associated with the eczema. She had tried all types oftreatments, including cortisone with no significant effect. Sheinitially used a topical preparation prepared according to thisinvention. This contained a mixture of low and high molecular weightsodium hyaluronate (prepared as in EXAMPLE 1) mixed with 1% WintergreenOil, 1% Spearmint Oil, and 0.5% Peppermint Oil. She applied it topicallyfor four weeks. She noted that the bright redness of the eczemasubsided. However, there was still itching and redness. She then beganto orally take the 1% mixture of low and high molecular weight sodiumhyaluronate described in example 1. She reported that within 2 weeks allsigns of the eczema had disappeared, the itching was gone and she feltbetter than she had felt for years. The oral dose required was 5 mg TIDfor this 91 pound female. Therefore, the dose was 0.05 mg/Kg. Thisdemonstrates that the complex carbohydrates of the present invention iseffective in treating severe cases of eczema even when they arecomplicated with a yeast infection.

EXAMPLE 15

[0087] In order to determine whether low doses of other complexcarbohydrates taken orally or mucosally could show effects similar tohyaluronic acid, 3 patients presenting with Lupus Erythematosis,interstitial cystitis and high blood pressure were treated with oralliquid chondroitin sulfate. None of these patients had taken chondroitinsulfate previously. A 5% (wt/vol) solution of chondroitin sulfate(Infinity Laboratories, Inc) without essential oils was prepared. Thiswas dispensed into 30 ml bottles and provided to the three patients withinstructions to take 1.0 mL orally BID, holding it in the mouth forapproximately 10 seconds prior to swallowing it. This represented a doseof 5 mg BID. The weight of the two patients were 155 lbs and 128 lbs,respectively. Therefore, the doses administered were 0.07 mg/Kg and 0.09mg/Kg. This provided relief (within 15 minutes). However, the relieflasted only 1-3 hours. The patients reported that they had to take thechondroitin Sulfate solution three to five times per day to obtainsuccessful treatment. After two months of this regimen, the patientswere given a mixture of the 5% chondroitin sulfate and 1% high molecularweight hyaluronic acid. They were instructed to take this as often asnecessary. Each reported that this product was effective when taken only2 times per day and the effect lasted from 8 to 10 hours for the Lupuspatient and for the interstitial cystitis patient. This demonstratesthat a mixture of low and high molecular weight complex carbohydrates ismore effective and that significantly lower doses (100 to 1000 fold lessthan currently suggested for OTC use) of chondroitin sulfate arerequired for more effective treatment of Lupus Erythematosis,interstitial cystitis and high blood pressure. Chondroitin sulfate iswidely known and used in tablets for arthritis. However, it is used forsuch treatment at very high doses (greater than 1000 mg per day). Wehave found that very low concentrations when administered in liquid formorally, mucosally or topically, is more effective than the higher dosesin a powder form. Additionally, the inventors are not aware of any useof chondroitin sulfate for any of our other indications of thetreatments and diseases listed.

EXAMPLE 16

[0088] A 55 year old female and a 56 year old male felt that they werecoming down with a cold. Both had oral sodium hyaluronate prepared asdescribed in EXAMPLE 1 available to them and began taking a 3 to 5 mgdose orally every 3 to 4 hours. They commented that the pain of the sorethroat was gone within 15 minutes of taking the oral preparation.Additionally, the cold seemed to be very mild and quickly progressedthrough the normal stages, each stage being much milder than normal forthese individuals. The female reported that her cold lasted only 4 daysas compared with her historical colds that lasted 21 to 24 days. Themale reported that he seldom noticed the symptoms of his cold and feltfine in 3 to 4 days. Historically, his colds lasted approximately 14days. These results indicate that the complex carbohydrates of thepresent invention reduce the symptoms of colds and that they haveanti-viral activity. ?5

EXAMPLE 17

[0089] In order to determine whether scar tissue could be reduced byapplication of the complex carbohydrates of the present invention.Sodium hyaluronate having a molecular weight range of between 10,000 and2 million was formulated so that it could be used as a scar reductionpatch. The formulation was prepared as follows: To 50 mL of 1% sodiumhyaluronate (Medex Ltd) was added 7 grams of alphy-hydroxy acid. Thesolution was mixed until a clear solution was produced. Then 20 mL ofUSP Glycerol was added and this was mixed to homogeniety. Finally, 1%sodium hyaluronate was added to QS the volume to a total of 100 mL.After the final HA addition, the solution thickened and was spreadevenly on the bottom of a petri dish. It was allowed to dry for 48 hoursat room temperature after which it was used to treat a fresh scarproduced as a result of reconstructive surgery on the left hand of a 50year old female patient. The solidified HA was cut into a shape slightlylarger than the scar. It was applied over the scar and held in place byapplying an ace bandage. Approximately ½ of the scar was left untreatedso as to serve as a control. The Bandage was allowed to remain over thescar for a period of 2 weeks. Intermittently, the HA patch was removedand the scar was cleaned. If the solidified HA patch dried out, it wasmoistened slightly with water and reapplied. After only two weeks ofapplication the raised scar tissue (adhesion) had essentiallydisappeared. This demonstrates that scar reduction can be accomplishedby use of the complex carbohydrates of the present invention

EXAMPLE 18

[0090] In order to determine whether open wounds could be stimulated toheal faster, gauze was soaked in 1% sodium hyaluronate having amolecular weight range from 30,000 to 500,000 and allowed to dry. ThisHA-containing gauze was applied to open wounds of the followingtypes: 1) a rug burn produced by sliding on artificial turf on afootball field; 2) a surgical wound resulting from a hip replacement;and 3) a cut finger resulting from a piece of broken glass. The bandageswere kept on the wounds until they were healed well enough to remainuncovered. It was reported that the rug burn was healed within 3 days.This compared with a 2 week healing period normally experienced by thispatient. The surgical wound healed within 5 days, again almost 10 dayssooner than expected. The cut finger was healed within 3 days. Theconclusion was that a glycosaminoglycan is very effective in stimulatingwound healing when incorporated into gauze and used as a bandage.

EXAMPLE 19

[0091] Ten patients taking oral preparations of 1% sodium hyaluronate (1taking low molecular weight ranging (from 10,000 to 300,000) 4 takingmedium molecular weight (ranging from 100,000 to 600,000), and 5 takinghigh molecular weight (ranging from 500,000 to 2 million),) reportedseparately that they had noticed the following positive effects inaddition to the treatment effects for which they were taking the complexcarbohydrate. They were impressed in the increased cognitive effectsthat they noticed. They reported that their memory had significantlyimproved as had their ability to focus on information and tasks(cognitive function) Additionally, each reported that they experiencedthickening of their hair and fingernails as well as improvement in theirskin condition (their skin was more supple and the wrinkles in theirface were reduced). These effects resulted directly from the use of thecomplex carbohydrates of the present invention.

EXAMPLE 20

[0092] Four of the patients taking oral or mucosal complex carbohydrates(1 taking 5% chondroitin sulfate and three taking 1% sodium hyaluronatewith a molecular weight range from 30,000 to 500,000) have reportedthat, prior to taking the complex carbohydrates of the presentinvention, they had been plagued with repeated vaginal yeast infections.All had been suffering from yeast infections at the initiation of thepresent treatment. They were not taking other medications to treat theseyeast infections. All four patients reported that their yeast infectionsdisappeared within 3 to 7 days of beginning treatment with the complexcarbohydrates of the present invention. They have remained on thepresent treatments for approximately 14 months and have remained yeastinfection free. It is concluded that the complex carbohydrates of thepresent invention are able to treat and/or prevent yeast infections.

[0093] All cited patents, provisional applications, publications and PCTapplications referred to in this application are herein incorporated byreference.

[0094] Although the invention has been described in detail in theforegoing, for the purpose of illustration it is to be understood thatsuch detail is solely for that purpose and that variations can be madetherein by those skilled in the art without departing from the spiritand scope of the invention except as it may be limited by the claims.

What is claimed is:
 1. A method of preventing and treating diseases andconditions associated with allergies, autoimmunity, the adhesioncascade, the metastatic cascade or the coronary cascade comprisingadministering (i) at least one complex carbohydrate as the sole activeingredient, or (ii) at least one pharmaceutical composition whichcomprises as an active ingredient a pharmacologically effective amountof at least one low purity or cosmetic grade complex carbohydrateselected from the group consisting of oligosaccharides, sialylatedoligosaccharides, polysaccharides and glycosaminoglycans, and at leastone transdermal or transmucosal carrier in an amount effective todeliver the complex carbohydrate into the blood stream.
 2. The method ofpreventing and treating diseases and conditions associated withallergies, autoimmunity, the adhesion cascade, the metastatic cascade orthe coronary cascade according to claim 1, comprising administering atleast one complex carbohydrate as the sole active ingredient.
 3. Themethod of preventing and treating diseases and conditions associatedwith allergies, autoimmunity, the adhesion cascade, the metastaticcascade or the coronary cascade according to claim 1, comprisingadministering at least one pharmaceutical composition which comprises asan active ingredient a pharmacologically effective amount of at leastone low purity or cosmetic grade complex carbohydrate selected from thegroup consisting of oligosaccharides, sialylated oligosaccharides,polysaccharides and glycosaminoglycans, and at least one transdermal ortransmucosal carrier.
 4. The method of preventing and treating diseasesand conditions associated with allergies, autoimmunity, the adhesioncascade, the metastatic cascade or the coronary cascade according toclaim 1, wherein said diseases and conditions comprise arthritis,gastritis, colitis, stomach or intestinal ulcers, colitis, esophagitis,bronchitis, the common cold, rhinitis, sore throat, tonsillitis,tendonitis, fibromyalgia, chronic fatigue syndrome, interstitialcystitis, polymyositis, autism, Lupus Erythematosis, headaches,pancreatitis, anaphylaxis, vaginitis, hemorrhoids, sunburn, heat burns,temporomandibular joint (TMJ) condition, gingivitis, dental caries,dental pain, post surgical pain, menstrual pain, extremity cramps, preand post partum pain, itching associated with allergies andhypersensitivity, asthma, emphysema, thrombosis, Attention DeficitDisorder, Attention Deficit Hyperactivity Disorder (ADHD), Turret'sSyndrome, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS) or LouGehrig's Disease, Parkinson's Disease, Bell's Palsy, cerebral palsy,peripheral neuropathy, high blood pressure, heart disease, heart attack,vasculitis, stroke, increased degradation of spinal nerves post spinalcord injury, head and brain trauma post injury, encephalitis, epilepsy,Guillain-Barre Syndrome, Human Immunodeficiency Virus infection (HIV),yeast infections, bacterial infections, viral infections, encephalitis,epilepsy, meningitis, peripheral neuropathy, Creuztfeldt-Jacob Disease,Bell's Palsy, cognitive disorder, adhesion formation post surgery orchemotherapy, scar formation post surgery, non-healing wounds, decubutisulcers, irritation of nerve ganglion formation, Alzheimer's disease,human immunodeficiency disease, bacterial infections, virus infections,yeast infections, meningitis, cancer, Diabetes, scleroderma, skinproblems and hair loss.
 5. The method of preventing and treatingdiseases and conditions associated with allergies, autoimmunity, theadhesion cascade, the metastatic cascade or the coronary cascadeaccording to claim 1, wherein the complex carbohydrates are selectedfrom the group consisting of oligosaccharides, sialylatedoligosaccharides, polysaccharides and glycosaminoglycans.
 6. The methodof preventing and treating diseases and conditions associated withallergies, autoimmunity, the adhesion cascade, the metastatic cascade orthe coronary cascade according to claim 1, wherein the complexcarbohydrates are administered orally, mucosally, parenterally ortopically.
 7. The method of preventing and treating diseases andconditions associated with allergies, autoimmunity, the adhesioncascade, the metastatic cascade or the coronary cascade according toclaim 1, wherein the complex carbohydrates are administered on arepeated basis for the term of the disease or condition to treat thedisease or condition and until said disease or condition is resolved. 8.The method of preventing and treating diseases and conditions associatedwith allergies, autoimmunity, the adhesion cascade, the metastaticcascade or the coronary cascade according to claim 1, wherein thecomplex carbohydrates are administered on a repeated basis as long asnecessary to prevent the diseases or conditions from developing or fromprogressing.
 9. The method of preventing and treating diseases andconditions associated with allergies, autoimmunity, the adhesioncascade, the metastatic cascade or the coronary cascade according toclaim 1, wherein a transdermal or a transmucosal carrier is added to thecomposition.
 10. A method for interrupting the adhesion cascade byblocking the ability of leukocytes to bind to blood vessel walls bycontacting complex carbohydrates with receptor sites on leukocytes toinhibit the ability of the leukocyte to bind to the blood vessel walls,thereby inhibiting the motility to the site of trauma and thus reducingpain and swelling.
 11. A method for inhibiting macrophages frominfiltrating areas of trauma on blood vessel walls thereby preventingthe formation of unstable plaques by administering complex carbohydratesin order to prevent or treat heart disease.
 12. A method for inhibitingT cell and macrophage infiltration into unstable plaques on blood vesselwalls thereby preventing the release of tissue factors that lead toheart attack or stroke by administering complex carbohydrates in orderto prevent said tissue factor release.
 13. A method for preventing ortreating allergies and allergy-related diseases and autoimmune diseasescontacting complex carbohydrates with receptor sites reactive cells toinhibit the ability of the reactive cells to bind to the blood vesselwalls, inhibiting allergic reaction and/or allergic response.
 14. Amethod of preventing or treating dementia by contacting complexcarbohydrates with receptor sites on cells of the brain so as to blockneuronal degradation produced by inflammation or amyloid proteins. 15.The method of claim 2, which comprises administering a mixture of highand low molecular weight sodium hyaluronate in an effective amount toprevent or treat acute or chronic fibromyalgia.
 16. The method of claim2, which comprises administering a mixture of high and low molecularweight sodium hyaluronate in an effective amount to prevent or treatAttention Deficit Hyperactivity Disorder.
 17. The method of claim 2,which comprises administering sodium hyaluronate in an effective amountto prevent or treat sunburn or pain associated with cervical discdegeneration or osteoarthritis.
 18. The method of claim 2, whichcomprises administering a mixture of high and low molecular weightsodium hyaluronate in an effective amount to prevent or treat coloncancer.
 19. The method of claim 2, which comprises administering amixture of high and low molecular weight sodium hyaluronate in aneffective amount to prevent or treat polymyositis.
 20. The method ofclaim 2, which comprises administering a mixture of high and lowmolecular weight sodium hyaluronate or chondroitin sulfate in aneffective amount to prevent or treat attention deficit disorder.
 21. Themethod of claim 2, which comprises administering low molecular weightsodium hyaluronate in an effective amount to prevent or treat AttentionDeficit Hyperactivity Disorder.
 22. The method of claim 2, whichcomprises administering a mixture of high and low molecular weightsodium hyaluronate or chondroitin sulfate in an effective amount toprevent or treat interstitial cystitis.
 23. The method of claim 2, whichcomprises administering sodium hyaluronate or chondroitin sulfate in aneffective amount to prevent or treat Lupus Erythematosis.
 24. The methodof claim 2, which comprises administering a mixture of high and lowmolecular weight sodium hyaluronate in an effective amount to alleviatepain resulting from ovarian cancer.
 25. The method of claim 2, whichcomprises administering sodium hyaluronate or chondroitin sulfate in aneffective amount to prevent or treat high blood pressure.
 26. The methodof claim 2, which comprises administering sodium hyaluronate in aneffective amount to prevent or treat lick granulomas.
 27. The method ofclaim 2, which comprises administering chondroitin sulfate andoptionally hyaluronic acid in an effective amount to prevent or treathot spots.
 28. The method of claim 2, which comprises administering amixture of high and low molecular weight sodium hyaluronate and at leastone essential oil in an effective amount to prevent or treat eczema. 29.The method of claim 2, which comprises administering a mixture of highand low molecular weight sodium hyaluronate in an effective amount toprevent or treat a cold.
 30. The method of claim 2, which comprisesadministering sodium hyaluronate in an effective amount to reduce scartissue.
 31. The method of claim 2, which comprises administering sodiumhyaluronate in an effective amount to stimulate healing of open wounds.32. The method of claim 2, which comprises administering sodiumhyaluronate in an effective amount to increase cognitive function, tothicken hair and fingernails, to increase suppleness of skin, or toreduce wrinkling of skin.
 33. The method of claim 2, which comprisesadministering sodium hyaluronate or chondroitin sulfate in an effectiveamount to treat or prevent yeast infections.
 34. The method of claim 2,wherein hypersensitivity is selected from the group consisting of poisonivy, oak and sumac and eczema and skin problems are selected from thegroup consisting of acne, lick granulomas, hot spots, psoriasis, rashes,and wrinkles.
 35. A bandage comprising at least one complex carbohydrateand at least one transdermal or transmucosal carrier effective foreffecting transdermal or transmucosal migration of said complexcarbohydrate, resulting in topical or mucosal delivery of saidmolecules, through the skin or mucous membranes of mammals and into thebloodstream.
 36. A bandage comprising at least one complex carbohydrateadded to or imbedded therein wherein said bandage is applied onto anarea requiring treatment.
 37. A method for blocking the ability of tumorcells to tether to blood vessel walls by contacting complexcarbohydrates with receptor sites on tumor cells to inhibit the abilityof the tumor cells to bind to the blood vessel walls, and inhibit thetumor motility which, in turn, inhibits the potential for metastasis.38. The method of claim 13, wherein the receptor sites are selected fromthe group consisting of CD44, CD31 and RHAMM.
 39. The method of claim13, wherein the reactive cells are white blood cells.
 40. The method ofclaim 14, wherein the complex carbohydrates of the present inventionbind to CD44, CD31 or RHAMM in the brain and inhibit the formation ofamyloid plaques.
 41. The method of claim 1, wherein prevention ortreatment results in blockage of receptor sites associated withallergies, autoimmune mechanisms, the adhesion cascade, metastaticcascade, or coronary cascade.
 42. The method of claim 1, wherein thecomplex carbohydrates bind to leukocyte receptor sites and/or bind toselecting, integrins, or other receptor sites that are involved with themechanisms by which leukocytes move to sites of trauma or that enablemetastasis of tumors and that, when bound, serve to inhibit the steps ofthe adhesion cascade, allergy or autoimmune mechanisms, the metastaticcascade, or the coronary cascade.